CONTROLLED RELEASE PREPARATION CONTAINING A SALT OF MORPHINE

Abstract: A new pharmaceutical preparation containing a number of coated particles comprising a salt of morphine coated with a barrier membrane providing a controlled, preferably pH-independent, release of morphine over the main part of the dose interval when administered once daily, providing a significantly reduced plasma concentration fluctuation compared to known morphine preparations. Also disclosed is a method for the manufacture of such a preparation and the use of such preparations for the manufacture of an analgesic useful in the treatment of severe chronical pain.

Description: Controlled relase preparation containing a salt of morphine . Field of invention The present invention relates to a new pharmaceutical preparation containing a nu ber of coated particles comprising a salt of morphine coated with a barrier membran with a controlled release of morphine over the main part of the dose interval when administered once daily, providing a significantly reduced plasma concentration flu tuation compared to known morphine preparations. The invention is also related to method for the manufacture of such a preparation and the use of such preparations for the manufacture of an analgesic useful in the treatment of severe chronical pain. Background of the invention Morphine has a serum half-life of 2-4 hours and the duration of its analgesic effect is about 4-6 hours after oral administration. The short duration makes it necessary to administer morphine orally 4-6 times daily to achieve a satisfactory analgesic effect. This has led to a development of various oral controlled release formulations of mor phine. Oral controlled release products containing morphine on the market e.g. MST Continue® or MS Contin® and Dolcontin®, are in general administered 2-3 times a day in order to give a sufficient pain relief over the entire dosage interval. Conventional matrix tablets consisting of morphine and an inert carrier composition are characterized by a fast initial drug release leading to an early peak of morphine plasma concentration followed by a decrease in release, which will be especially pro nounced in the lower intestinal system where more neutral or weakly basic conditions prevail. There has been a demand to find a way to obtain an oral drug preparation having a more even release of morphine in order to get smoother blood concentration and effect profiles over the entire dosage interval when administered once daily. EP-B-0097523 discloses such a preparation where the drug is distributed in a contro led release matrix partly in the form of a salt and partly as a free base. This prepara- tion increases dissolution time and biovailabilty without the need of applied coating membranes. It is known that morphine gives considerable problems in the development of matri tablets which have been considered to be due to poor absorption properties of mor- phine in the distal parts of the gastrointestinal tract, see Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 18, 1991, pag.433-434, (B. Olsson et al). There are several examples of formulations which are designed to overcome the drawbacks of oral matrix tablets by providing a constant or controlled release rate over a more extended period. An example of such formulations is multiple unit (MU) formulations as disclosed previously in EP-A-0080341 and in WOA-91/01722. The depot preparation consisting of a large number of small units is considered to promote good absorption properties by being dispersed over a large area in the gas trointestinal tract and having a lower transit rate especially in the colon, compared matrix tablets, see Drug Delivery to the Gastrointestinal Tract, Ed. By JG Hardy Et. Chichester, Ellis Howard Ltd, 1989, pages 75-81: "Colonic transit rate and drug deli very". In addition multiple unit formulations are preferable to one single unit as th may be divided into smaller portions all having the same release and absorption pr perties which will give greater flexibility in selection of the size of the dose, will fac litate administration of the drug to patients having problems to swallow and will c siderably reduce the risk of dose dumping. Also in EP-A-0377518 there is described a sustained release pellet formulation, bu with core elements which may comprise the salt of a morphine compound coated with a hybrid coating admitting a slow release at an acidic pH and relatively consta higher release at a less acidic to basic pH. The preparations according to EP-A-037 518 exhibit a limited bioavailibility, restricting the administration to at least twice daily. ZA-A-921366 relates to a solid controlled release dosage form for improved storage stability at elevated temperature and/or elevated relative hunidity. The controlled release is obtained by overcoating a substrate including a therapeuticaliy active ing dient with a coating derived from an aqueous dispersion of ethylcellulose and then curing the coated substrate at an elevated relative humidity and at a temperature above the glass transition temperature for the coating. There is no indication in ZA- 921366 that any of the preparations would be suitable for a once daily administratio Description of the invention The object of the present invention is to provide a once-daily preparation of morphi i.e. a preparation with an even blood concentration profile when the preparation is administered once daily, without any substantial loss in bioavailability. The preparation should preferably also have a release rate of morphine which is su stantially independent of its position in the gastrointestinal tract. Such a preparation represents an improvement in the treatment of severe opioid se sitive pain and supplies a convenient oral dosage form which gives an even effect a reduced risk of pain breakthrough. The present invention is related to a multiple unit preparation of morphine consisti of small particles of morphine salts and a coated barrier layer which preferably pro des a pH independent release, methods for their manufacture and the use of such preparations for the treatment of severe opioid sensitive pain by a once daily admi stration. In general, a multiple unit preparation contains of at least 50, and suitably of at leas 150, individual drug including particles, e.g. crystals, beads or pellets. A multiple u preparation in accordance with the present invention has a controlled rate of drug release during 15 - 24 hours for all possible strengths of the preparation in the prefe red interval of 10-400 mg morphine (salt). However, higher total dosages of morphi are conceivable in certain applications and those will also be possible to administer with the multiple unit preparation according to the present invention. This means that a multiple unit preparation to fulfil the criteria of the invention shall give seru concentrations greater than or equivalent to 50% of the maximum concentration during at least 12 hours, suitably for at least 18 hours and preferably for at least 24 hours. A multiple unit preparation according to the present invention should suitably give a serum concentration greater than or equivalent to 40% of the maximum concentration during at least 18 hours, and preferably for at least 24 hou This means that the preparations of the present invention can be advantageoulsy u for dosage intervals up to 24 hours, most preferably for once-daily administration, less preferably for twice-daily administration. Other objects of the present invention are low peak plasma concentration of morph ne, release of 50% of the total dose within 4-10 hours and more than about 80%, pr ferably more than 90%, bioavailability of the preparation when compared to tratditi nal preparations as instant release tablets and oral solutions. It has been found that these demands are met surprisingly well by a preparation co taining a large number of small particles comprising a salt of morphine which are coated with a barrier layer containing at least one component insoluble in the fluid of the gastrointestinal system to provide high serum concentrations for a prolonge period of time. The particles contain a salt of morphine and optionally pharmaceutically acceptabl exάpients such as lactose and microcrystalline cellulose and have a size of 0.2 to 3 mm, preferably 0.7 to 1.4 mm. Suitable salts of morphine are soluble salts, such as morphine hydrochloride, morphine sulphate, and salts of certain organic carboxyli acids. The particles are prepared with conventional methods such as mixing and gr nulation of the morphine salt with the exάpient or exάpients, extrusion, spheroniz tion, drying and sieving the particles to an acceptable size range. Examples of suitable barrier coating materials which are substantially insoluble in t fluids of the gastrointestinal tract are natural and synthetic polymers such as ethyl cellulose, Eudragit RS, polyvinyl chloride, natural or synthetic waxes as carnauba wax. Ethyl cellulose is an especially suitable insoluble material which is available in diff rent grades and in special qualities for aqueous based barrier coatings. According t the invention it is preferable to use ethyl cellulose having a viscosity of 5 to 15 cps, but also other types of cellulose may be used. In a barrier coating preferred according to the present invention, the water insolubl component or components will be mixed with one or several components soluble i water. Suitable water soluble components are polymers like hydroxypropylmethyl cellulose, hydroxypropyl cellulose, Eudragit RL and Eudragit NE. Instead of water soluble polymers other water soluble substances as sugar, lactose and different salt can be used in the formation of a partly erodable film with a pH-independent relea rate. Eudragit is the trade name of a substance useful for film coating of controlled relea particles, which can be both soluble and insoluble in the fluids of the gastro intestin tract (see above). Eudragit RL and RS (Rohm Pharma) are copolymers synthesised from acrylic and methaσylic esters with a low content of quaternary ammonium groups. Eudragit RL and RS differ in the molar ratios of the ammonium groups to t remaining neutral (meth)acrylic acid esters (1:20 and 1:40 respectively). Eudragit N is the aqueous dispersion of a neutral copolymer based on ethyl aαylate and methy methaσylate. These above mentioned properties result in cLifferent permeability characteristics. The coating procedure can be performed by conventional means such as a spraying equipment, a fluidised bed and equipment for drying and size fractionating. The liquid used in the coating procedure contains one or several barrier layer forming components and one or several solvents, such as ethanol, acetone, methyl isobutyl ketone (MIBK), water and others well known in this technical field. The coating liqu can be in the form of a solution, a dispersion, an emulsion or a melt, depending on t specific nature of the coating constituents. Plasticizers and pigments may optionally be used to modify the technical properties or change the permeability of the coating. The coating membrane is made of one or more polymers and has preferably a virtually pH independent permeability proper ties within the pH range of 1.0 to 7.0. At higher pH a reduction in the release of mor phine may be observed but this is not due to the properties of the polymeric layer b depends on the reduced solubility of morphine salts at high pH values. A characteristic and suitable coating composition within the scope of invention cons sts of ethyl cellulose and hydroxypropylmethyl cellulose anda certain amount of tri ethyl citrate as plasticizer. A specific example of the coating composition is ethyl cel lulose and hydroxypropylmethyl cellulose in relations from 55/35% to 80/10% w/ with 10% triethyl citrate as a plasticizer. Each coated morphine particle represents an individual controlled release unit, rele ing the drug at a predetermined rate preferably independent of its position in the ga trointestinal tract. Coated pellets according to the invention can be used in different types of dosage forms such as gelatine capsules, compressed tablets or sachets. The invention makes it possible to obtain a dosage form of morphine salts that can given once daily and still produce almost constant plasma concentrations of the dru and a high biological availability. Detailed description of the invention The following examples are intended to illustrate suitable preparations within the scope of invention, which meet the demands set on the oral morphine formulations the previous text. The examples shall not be regarded as limiting for the scope of invention and alterations and modifications of parameters and ingredients can be made without departing from the context of the present invention. Example 1 Manufacturing of morphine pellets Morphine hydrochloride pellets to be used in a controlled release preparation acco ing to the present invention can be manufactured by the following measures. Morphine hydrochloride was selected as a suitable salt for the formulation work. I has very similar properties to the most common alternative morphine sulphate, regarding e.g. water solubility. Fuiiher studies showed that the solubility is not cri cally dependent on the pH-value of the dissolution medium (within the physiologi range). This is in accordance with its high pKa-value (7.5). Microαystalline cellulose is a common diluent in pellet formulations as it gives ver good technical properties. Lactose is used as a soluble constituent. 1. Mixing and granulating: Morphine hydrochloride (40 % w/w), lactose (40 % w/ and rrdσocrystalline cellulose (Avicel PH-101) (20 % w/w) totally 1500 gram were dry-mixed in a planetary type mixer (Kenwood Major) at a low mixing speed (spe adjustment <1) for 10 minutes. Water (585 gram ) was added and the mass was granu-lated for 5 minutes at speed adjustment 2. 2. Extrusion: Extrusion was performed in a NICA E-140 extruder (Lejus Medical A Sweden) through a perforated screen with drilled orifices of 1.0 mm diameter. The speed of the agitator and the feeder were set on the lowest values. 3. Spheronization: Spheronization was conducted in a marumerizer (Ferro Mecano AB, Sweden). The speed of the marumerizer plate was adjusted to 450 rpm. The nu ber of spheronization rounds were 5, with about 400 grams of wet extrudates on th plates at each run. 4. Drying: Drying was performed in a fluid bed dryer (Aeromatic AG West Germa at an IN-temperature of 50°C. The batch was divided into sub-batches of 600-700 grams wet particulate cores. Each sub-batch was dried for 5 minutes at the air velo adjustment 20 in order to obtain individual cores rather than aggregates. The sub- batches were then mixed and the whole batch was dried at adjustment 12 for 65 minutes. The end OUT-temperature was 36°C. The yield of dry cores after drying 1437 gram and 96% w/w. 5. Sieving: Sieving was performed by using analytical sieves with sieve sizes of 0.71 mm and 1.40 mm, respectively. The yield of dry cores after sieving was 1337 gram and 89% w/w. The yields were 96 and 89 % w/w after drying and sieving, respectively. The mass was lost during the extrudation and sieving procedures. A sieving analysis before and after abrasion of the cores showed that about 93% of cores had a size between 0.71 and 1.0 mm. A crushing strength analysis showed th the mean crushing strength of 1.0 mm particles was 4.71 N. A hardness value at thi level makes it possible to coat the particles in a small as well as in a larger equipme The obtained morphine hydrochloride cores are well suitable for production in lar scale. Example 2 Coating of morphine hydrochloride pellets Morphine hydrochloride cores manufactured in accordance with Example 1 can be coated with controlled release membranes to prepare multiple unit formulations within the scope of the present invention. Hydroxypropylmethyl cellulose (HPMC) E5 and ethyl cellulose (EC) 10 cps were used as film formers together with triethyl citrate (TEC) as a plasticizer. The coating solution contained 99.5% ethanol and methyl isobutyl ketone (MIBK). The coating was performed using a spray coating equipment (NICA FB-coater, Sweden). The spray gun used was a Binks & Bullows with a J92R liquid nozzle and J930 air nozzle. A net device was placed in the top of the fluidised bed to avoid los of cores to the cyclone output. The spray gun was mounted on a height over the bottom of the bed of 185 mm. Ethanol/MIBK mixture was pumped through the system prior to the start of the coating, and there was consequently liquid present between the pump housing and the spray gun. The morphine hydrochloride cores prepared as in Example 1 were loaded. The cores were pre-heated at 55°C with an air velocity of 20-25 rn^/h for 4 minutes: At the start of the coating, the bed temperature was 32-36°C. The coating was started using the following process parameters: atomising pressur 500 kPa, air velocity 85 m 3 /h and a solution flow of about 24 ml/min. The register IN-temperature varied between 53 and 56°C, the OUT-temperature between 34 and 38°C during the coating. Morphine hydrochloride cores from the same batch were coated with different pro¬ portions of EC/HPMC in the film coating solution. Different amounts of the polym solution was also tested in order to obtain a suitable in-vitro dissolution rate at a su able film thickness ( too thin a film may give reproducibility problems), see Table 1 below. A mixture of 5.5 parts of EC and 3.5 parts of HPMC was selected and an amount of approximately 8 mg of coating material per capsule content (approximately 7.5%w per dose) was f ound to be suitable. it is well known, however, that the amoimt of polymer will vary considerably with rather small variations in the mean pellet size (or surface area), which means that a careful optimisation must be done for each produced pellet quality to ensure an adequate dissolution rate. The coated spheres were sieved through a 1.4 mm sieve and spheres with a size les than 1.4 mm are collected. The collected spheres were filled into hard gelatine caps les (Hard gelatine capsule, colour white. No. 2) with a normal weight of 0.17 g (net weight 108 mg). The capsules meet the requirements of the mass uniformity test in Ph. Eur. The mean content of active component in the capsules are between 36 and mg. The composition per capsule was: Morphine hydrochloride 40 mg Lactose 40 mg Microcrystalline cellulose 20 mg Water (purified), evaporated during the process q.s. Ethyl cellulose (EC) 3.5-5.3 mg Hydroxypropyl methylcellulose (HPMC) 2.2-3.4 mg Triethyl citrate (TC) 0.6-1.0 mg Ethanol 99.5% (evaporated) q.s. Methyl isobutylketone (evaporated) q.s. Hard gelatine capsule, white. No.2 approx.60 mg The film components are selected to give release properties that are virtually indep dent of pH and agitation. At very high pH-values, the release rate is reduced as expected when considering t pKa-value of morprtine hydrochloride (see Tables 2 and 5). The agitation speed had no significant effect on the release rate (see Tables 2 and 6) The in-vitro dissolution test is carried out with the USP dissolution apparatus No. (paddle) at 50 rpm, 37°C, in a phosphate buffer solution, pH 6.8. Six individual caps les are tested. The amount released (% of labelled amount) is calculated : <15% released after 1 h 35-65% released after 6 h 55-80% released after 12 h not less than 80% released after 24 h Table 1 In vitro dissolution rate. Morphine hydrochloride pellets according to above, but different amounts and proportions of polymers in the coating. Method: USP dissolution apparatus No. π (paddle) at 50 rpm, 37°C, in a phosphate buffer solution, pH 6.8. Amount of film (%w/w) 1.4 2.7 8.0 2.7 Prop:EC: HPMC.TEC 8:1:1 8:1:1 8:1:1 7:2:1 Time per cent dissolved morphine (hours) hydrochloride, n=2 1 2 3 4 5 6 7 8 10 12 24 106 97 64 102 EC; ethylcellulose HPMC; hydroxypropyl methylcellulose TEC; triethyl citrate *) n=6 Table 1 continuation Amount of film (%w/w) 4.2 4.6" 7.5* Prop:EC: HPMC.TEC 7:2:1 5.5:3.5:1 5.5:3.5:1 Time per cent dissolved morphine (hours) hydrochloride, n=2 1 2 3 4 5 6 7 8 10 12 24 EC; ethylcellulose HPMC; hydroxypropyl methylcellulose TEC; triethyl citrate *) n=6 Table 2 In vitro dissolution rate: Morphine hydrochloride pellets according to above with a coating of EC : HPMC : TEC = 5.5 : 3.5 : 1 at different agitation speed and pH. Method: USP dissolution apparatus No. π (paddle), 37°G Dissolution pH 6.8 pH 6.8 pH 1.2 pH 4.0 pH 7.6 media n=6 n=6 n=3 n=4 n=3 Agitation 50rpm 100rpm 50rpm 50rpm 50rpm speed Table 3 In order to compare the in vitro dissolution rate at different pH, coating film thickness, agitation speed and temperature, the preparation of the following composition was prepared in a comparable manner to the manufacturing procedur above. Proportion of EC : HPMC : TEC = 8 : 0.5 : 1.5 Active constituent Morphine hydrochloride 20 mg *Evaporated during the manufacturing process Table 4 In vitro dissolution rate. Morphine hydrochloride CR pellets with different amoun polymers in the coating. Proportions EC : HPMC : TEC = 8: 0.5 : 1.5 Method: USP dissolution apparatus No. II (paddle), 37°C dissolution medium phosphate buffer, pH=6.8, agitation speed 50 rpm. EC; ethylcellulose HPMC; hydroxypropyl methylcellulose TEC; triethyl citrate * n=3 Table 5 In vitro dissolution tests: Morphine hydrochloride CR according to Table 3 at different pH. Method: USP dissolution apparatus No. II (paddle), 37°C, dissolution agitation speed 50 rpm. Table 6 In vitro dissolution rate. Morphine hydrochloride CR pellets batch according to Ta 3 at different agitation speed. Method: USP dissolution apparatus No. π (paddle), 37°C, dissolution medium phosphate buffer, pH 6.8. Agitation speed 40rpm 50rpm lOOrpm Time per cent dissolved morphine (hours) hydrochloride, n=6 1 2 3 4 6 8 10 12 15 18 21 24 Table 7 In vitro dissolution rate. Morphine hydrochloride CR pellets batch according to Ta 3 at different temperatures. Method: USP dissolution apparatus No. π (paddle), dissolution medium phosphate buffer, pH 6.8, agitation speed 50 rpm. As shown in Table 4 it is possible to control the release rate by varying the amount film coating on the pellets. These experiments show that adequate dissolution rates are obtained and thus ma it possible to fulfil the requirements set on the preparations. The film components were selected to give release properties that are virtually ind pendent of pH and agitation. By testing the in vitro dissolution rates of the pellets different batches (see Tables 1-7), the composition of which can be seen in Table 3. testing the pellets under different conditions (see Tables 2 and 5-7) it is verified tha only small variations in dissolution at pH:s appear and that changes in agitation speed and temperature had no significant effect on the release rate. Example 3 Bioavailability study A single dose, 3-way crossover bioavailability study was performed in 6 healthy individuals. Two prototypes of Morphine controlled release (CR) capsules manu¬ factured in accordance with Examples 1 and 2 of the present invention were studie see also Tables 8 and 9, below. A morphine oral solution was used as a reference p paration. The subjects received either 30 mg of CR capsule A, 40 mg of CR capsule or 15 mg of the solution after an overnight fast. Venous blood samples were drawn prior to and during 32 hours after drug administration, Determination of morphin in serum was performed using a specific LC-method with electron capture detectio The arfea under the serum concentration of morphine vs. the time curve (AUC), the maximum serum concentration, C ax, the time to reach maximum serum concen¬ tration, tmax, the width of the serum concentration vs time curve at half the Cmax concentration (W50) and the relative bioavailability of the CR capsules, (F re ι) was calculated. The results are presented in Table 10 below. The following preparations were used in the study: Morphine CR capsules 30 mg formulation A, prepared according to Examples 1 an 2; morphine CR capsules 40 mg formulation B, prepared according to Examples 1 a 2 and morphine oral solution formulation C, 5 mg/ml, as a reference. Table 8 Constituent Morphine hydrochloride Lactose Microσystalline cellulose Water (purified), evaporated in the process Ethylcellulose (EC) Hydroxypropyl methylcellulose (HPMC) Triethyl citrate (TC) Ethanol 99.5% (evaporated) Methyl isobutylketone (evaporated) The in vitro dissolution rates at pH 6.8 are presented in Table 9. Table 9 In vitro dissolution rate of the CR capsules at pH 6.8 Time % dissolved 102 83 95 Table 10 Results of a bioavailability study of healthy volunteers: Parameter Capsule A 30 mg Capsule B 40 mg Solution 15 mg The results of the study show very good bioavailability of both CR capsule prepar tions tested. Capsule A with a dissolution rate profile which makes it suitable for twice daily administration, showed a bioavailability of approximately 100% compa ed to the solution. Capsule B, with a dissolution rate profile intended for once dail administration showed a slightly lower bioavailability (approx. 90%). However, at last sampling point (32 hours) the serum concentrations were, in this case, still abo half the Cmax concentration and the true bioavailability was thus higher than the c culated figure. The curve width at half the Cmax concentration W50 was about 5 times larger for Capsule A than for the solution. For capsule B W50 was at least 15 times larger tha for the solution. This, in combination with the excellent bioavailability shows that morphine can be administered once daily in a multiple unit preparation according the invention and that such a preparation will result in low fluctuations in the seru concentration profiles. This can be seen in Figure 1 which shows mean serum concentrations in the six test individuals versus time for the three preparations A, B, and C. It is obvious from t figure that preparation B, according to the invention, gives almost constant plasma concentrations during 24 hours.

Claims: Claims 1. An oral pharmaceutical preparation containing a therapeutically effective amou of a salt of morphine for administration once daily characterized in that it consists a plurality of particles each having a core containing a salt of morphine coated wit barrier layer containing at least one water insoluble compound and in that the mea serum concentration of morphine obtained is at least 50 % of the maximum serum concentration during at least 12 hours after the administration of a single dose of s preparation. 2. A preparation according to claim 1 characterized in that the mean serum concen tration of morphine obtained is at least 50 % of the maximum serum concentration during at least 18 hours after the administration of a single dose of said preparatio 3. A preparation according to claims 1 or 2 characterized in that the drug release through the coating barrier layer is substantially independent of pH within the ran 1.0 to 7.0. 4. A preparation according to any previous claim characterized in that the size of particles is in the range of 0.2 to 3 mm, preferably between 0.7 and 1.4 mm. 5. A preparation according to any previous claim characterized in that the water insoluble component is selected from the group consisting of ethyl cellulose, copol mere synthesized from acrylic and methaαylic esters, polyvinyl chloride and certai natural or synthetic waxes. 6. A preparation according to any previous claim characterized in that the coating barrier layer also contains at least one water soluble component selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, cop mers synthesised from acrylic and methaαylic acid esters, suitable sugars, and salt and optionally plastiriLzers and/or pigments. 7. A preparation according to claim 6 characterized in that the coating barrier laye contains ethyl cellulose, hydroxypropylmethyl cellulose and triethyl citrate as a plasticizer. 8. A preparation according to any previous claim characterized in that the salt of morphine is chosen among morphine hydrochloride, morphine sulphate and morp ne salts of suitable carboxylic acids. 9. A preparation according to any previous claim characterized in that it is in the form of a tablet, a capsule or a sachet. 10. A process for the manufacture of the preparation according to any previous clai characterized by that the morphine containing particles are subjected to a spray co ing procedure in a fluidized bed with a solution, dispersion or a suspension of coat ing solution containing a mixture of components which provides a pH-independen barrier coating on the particles and thereafter dried, size fractionated and collected. 11. A process according to claim 10 characterized by that the morphine containing particles are prepared by granulating a salt of morphine together with one or sever exάpients and a granulating fluid, extruding the granulated product and thereafte subjecting it to spheronization, drying and size fractionating. 12. Use of the preparation according to any of claims 1-9 for manufacturing a med cament for a once daily oral treatment of a severe opioid sensitive pain which dem ds a low plasma fluctuation of morphine. 13. A method for the treatment of severe opioid sensitive pain characterized by ad nistering to a patient a medicament containing any of the preparations according t claims 1-9 once daily.

Inventors: OLSSON BIRGITTA, PESONEN MARITTA ANNELI, RAGNARSSON GERT, OLSSON, BIRGITTA, PESONEN, MARITTA, ANNELI, RAGNARSSON, GERT
Applicants: KABI PHARMACIA AB, OLSSON BIRGITTA, PESONEN MARITTA ANNELI, RAGNARSSON GERT, OLSSON, BIRGITTA, PESONEN, MARITTA, ANNELI, RAGNARSSON, GERT
Application year: 1994
Main classification: A61K9
IPC codes: A61K9, A61K31, A61K47, A61P25